TCRαβ-depleted Progenitor Cell Graft With Additional Memory T-cell DLI, Plus Selected Use of Blinatumomab, in Naive T-cell Depleted Haploidentical Donor Hematopoietc Cell Transplantation for Hematologic Malignancies

In this study, participants with high-risk hematologic malignancies undergoing hematopoietic
cell transplantation (HCT), who lack an available suitable human leukocyte antigen (HLA)
matched related/sibling donor (MSD) or matched unrelated donor (MUD), will receive a
TCRαβ-depleted haploidentical donor HCT with additional memory cell DLI. One course of
blinatumomab will be empirically added for patients with CD19+ malignancy.

Primary Objectives

- Determine the maximum effective dose for prophylactic CD45RA-depleted DLI when given in
the early post-engraftment period.

- Assess the efficacy of TCRαβ-depleted progenitor cell graft with additional memory
T-cell DLI, plus selected use of blinatumomab, in haploidentical donor hematopoietic
cell transplantation for hematologic malignancies as measured by 1 year EFS (events =
relapse, death) Secondary Objectives

- Assess the safety and feasibility of the addition of blinatumomab in the early post-
engraftment period in patients with CD19+ malignancy

- Estimate the cumulative incidence of:

- neutrophil engraftment at Day +30

- platelet engraftment at Day +100

- acute GVHD at Day +100

- chronic GVHD at 1 year

- transplant related mortality (TRM) at Day +100

- malignant relapse at 1 year

- Estimate 1yr event-free survival per disease subgroups (ALL vs AML)

- Estimate 1yr overall survival at one-year post-transplantation. Exploratory Objectives

- Record immune reconstitution parameters, including chimerism analysis, quantitative
lymphocyte subsets, T cell receptor excision circle (TREC) analysis, V-beta
spectratyping, and lymphocyte phenotype and function. All analysis will be descriptive
only.

- Describe the use of additional CD45RA-depleted DLI for recipients who have severe viral
infections, disease recurrence or progression, or poor immune reconstitution. Assess and
record efficacy of CD45RA-depleted DLI for these conditions, and all adverse events that
are related to CD45RA-depleted DLI. All analysis will be descriptive only.

Additional Information:

Blinatumomab will be given to patients with a history of CD19+ malignancy as determined by
St. Jude hematopathologist review of current and historical specimens and reports.
Blinatumomab dosing will begin no sooner than 1 week after CD45RA-depleted DLI and no later
than Day +90. There must be no acute GVHD or it must be quiescent. ALT must be less than 5x
ULN, bili less than or equal to 1.5x ULN, and creatinine less than or equal to 1.5x ULN.

If more than one family member donor is suitable, then donor selection will be based on
several factors including: degree of KIR mismatching, donor-recipient matching of CMV
serology, donor-recipient red blood cell compatibility, degree of HLA matching, size of the
potential donor, previous use as a donor, presence of donor-specific antibody, and overall
health and availability of the potential donor.

A G-CSF mobilized peripheral blood progenitor cell product (identified as HPC,A) is the
preferred progenitor cell graft source. Our desired target goal will be 5 x 10^6 CD34+
cells/kg. This number of cells will be necessary to provide an adequate graft, following the
various ex vivo manipulations, for prompt reconstitution. More than one collection may be
needed to achieve this goal. Donors will undergo a standard hematopoietic progenitor cell
mobilization regimen consisting of 5 days of GSF given subcutaneously at 10
micrograms/kilogram. The graft will be collected by leukapheresis on day 5 (and 6 if needed)
of G-CSF. The HPC product will typically be collected and infused fresh, however there may be
patients or logistical situations that require the HPC product to be collected early,
processed, and stored frozen.

Inclusion Criteria for Transplant Recipient

- Age less than or equal to 21 years.

- Does not have a suitable HLA-matched sibling donor (MSD) or volunteer 10/10
HLA-matched unrelated donor (MUD) available in the necessary time for progenitor cell
donation.

- Has a suitable single haplotype matched (≥ 3 of 6) family member donor.

High risk hematologic malignancy. High risk ALL in CR1. Examples include, but not limited
to: t(9;22) with persistent or recurrent transcript, hypodiploid cytogenetics, MRD >1% at
the end of induction, M2 or greater marrow at the end of induction, recurrent or rising MRD
after induction, Infants with MLL fusion or t(4;11), relapse after prior CART therapy.

ALL in High risk CR2. Examples include, but not limited to t(9;22), BM relapse <36 mo CR1
or <6mo after completion of therapy, any T-ALL, very early (< 6mo CR1) isolated CNS
relapse, late BM relapse with poor response to standard reinduction therapy(e.g. MRD
positive or recurrence after two blocks), relapse after prior CART therapy.

ALL in CR3 or subsequent.

AML in high risk CR1 (diagnosis of AML includes myeloid sarcoma). Examples include but not
limited to: preceding MDS or MDS-related AML, FAB M0, FAB M6, FAB M7 with high risk
genetics such as ML not t(1;22), MRD > 0.1% after two cycles of induction, MRD > 1% after
one cycle of induction, FLT3-ITD in combination with NUP98-NSD1 fusion or WT1 mutation, any
high risk cytogenetics such as: DEK-NUP214 [t(6;9)], KAT6A-CREBBP [t(8;16)], RUNX1-CBFA2T3
[t(16;21)], -7, -5, 5q-, KMT2A-MLLT10 [t(6;11)], KMT2A-MLLT4 [t(10;11)], inv(3)(q21q26.2),
CBFA2T3-GLIS2 [inv(16)(p13.3q24.3)], NUP98-KDM5A [t(11;12)(p15;p13)], ETV6-HLXB
[t(7;12)(q36;p13)], NUP98-HOXA9 [t(7;11)(p15.4;p15)], NUP98-NSD1.

AML in CR2 or subsequent.

- Therapy related AML, with prior malignancy in CR > 12mo

- MDS, primary or secondary

- NK cell, biphenotypic, or undifferentiated leukemia in CR1 or subsequent.

- CML in accelerated phase, or in chronic phase with persistent molecular positivity or
intolerance to tyrosine kinase inhibitor.

- Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or unable
to mobilize progenitor cells for autologous HCT.

- Non-Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or
unable to mobilize progenitor cells for autologous HCT.

- JMML

- If prior CNS leukemia, it must be treated and in CNS CR

- Does not have any other active malignancy other than the one for which this HCT is
indicated.

- No prior allogeneic HCT, and no autologous HCT within the previous 12 months.

Patient must fulfill pre-transplant organ function criteria:

- Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%.

- Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2.

- Forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room
air if patient is unable to perform pulmonary function testing.

- Karnofsky or Lansky (age-dependent) performance score ≥ 50 (See APPENDIX A).

- Bilirubin ≤ 3 times the upper limit of normal for age.

- Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 5 times the upper
limit of normal for age.

- Not pregnant. If female with child bearing potential, must be confirmed by negative
serum or urine pregnancy test within 14 days prior to enrollment.

- Not breast feeding

- Does not have current uncontrolled bacterial, fungal, or viral infection.

Inclusion Criteria for Haploidentical Donor

- At least single haplotype matched (≥ 3 of 6) family member

- At least 18 years of age.

- HIV negative.

- Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days
prior to enrollment (if female).

- Not breast feeding.

Regarding donation eligibility, is identified as either:

- Completed the process of donor eligibility determination as outlined in 21 CFR 1271
and agency guidance; OR

- Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent
medical need completed by the principal investigator or physician sub-investigator per
21 CFR 1271.

Exclusion Criteria: